System and methods for therapeutic stimulation

ABSTRACT

A system and method for providing electrical stimulation to biological tissue to treat medical conditions. The system can include a lead configured to be positioned in contact with biological tissue proximate one or more occipital nerves, an implantable pulse generator configured to deliver electrical stimulation to the biological tissue via the one or more leads, and/or a power source configured to operatively connect and supply power to the implantable pulse generator. The system can further include a processor configured to communicate with the implantable pulse generator. The processor can operate the implantable pulse generator to deliver the electrical stimulation to the biological tissue via the lead. The implantable pulse generator can deliver the electrical stimulation by applying a stimulation waveform or a stimulation pattern. The stimulation waveform can include a series of stimulation pulses that can vary over time, which can reduce an effect of neural accommodation or adaptation.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims priority benefit to U.S. ProvisionalApplication No. 62/489,925, filed Apr. 25, 2017, entitled “SYSTEM ANDMETHODS FOR THERAPEUTIC STIMULATION,” which is hereby incorporatedherein by reference in its entirety. Any and all applications for whicha foreign or domestic priority claim is identified in the ApplicationData Sheet as filed with the present application are hereby incorporatedby reference under 37 CFR 1.57 and made a part of this specification.Any and all publications or patent applications mentioned herein arehereby incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

BACKGROUND Field of the Invention

The present disclosure relates to systems and methods of electricalstimulation, which can be utilized to treat medical conditions and/ordisorders.

Description of the Related Art

Many people around the world are afflicted by chronic neurologicaldisorders including, but not limited to, Chronic Pain, Parkinson's,Essential Tremor, Urinary Incontinence, Heart Failure & Epilepsy.Electrical stimulation of the nervous system is widely used to treatthese chronic conditions. However, these therapies have numerousopportunities for improvement. For example, a large number of people inthe United States are afflicted with Chronic Migraine (“CM”), a highlydebilitating neurological disorder. While abortive and preventativemedicines exist, a significant part of the CM population are termedintractable and do not respond adequately to these treatments. It isestimated that over 318 thousand Americans suffer from IntractableChronic Migraine (“ICM”). These patients are highly disabled by theirdisease and are faced with a significantly lowered productivity andquality of life with few options for relief. These patients who areunresponsive to preventative medicine may progress to more invasive andproblematic therapies such as opioid injections, nerve blocks andsurgery. Techniques such as Occipital Nerve Stimulation (“ONS”) arepromising therapies for a variety of headache disorders such as CM andICM.

SUMMARY

A system for providing electrical stimulation to biological tissue totreat one or more medical conditions. The system can include one or moreleads configured to be positioned in contact with or proximate tobiological tissue that is proximate one or more occipital or peripheralnerves. The one or more leads can include one or more electrodes. Thesystem can further include an implantable pulse generator configured todeliver electrical stimulation to the biological tissue via the one ormore leads. In some cases, the implantable pulse generator can have asize of less than 5 cc and/or can be implanted directly in an occipitalregion of a patient or proximate the occipital region. The system canfurther include a power source configured to operatively connect andsupply power to the implantable pulse generator. The system can furtherinclude one or more processors configured to communicate with theimplantable pulse generator. The one or more processors can operate theimplantable pulse generator to cause the implantable pulse generator todeliver the electrical stimulation to the biological tissue via the oneor more leads. The implantable pulse generator can deliver theelectrical stimulation by applying a stimulation waveform or astimulation pattern. The stimulation waveform can include a series ofstimulation pulses that can vary over time, which can reduce an effectof neural accommodation or adaptation.

The system of the preceding paragraph may also include any combinationof the following features described in this paragraph, among othersdescribed herein. At least one of an inter-pulse frequency, a pulseamplitude, or a pulse width of the series of stimulation pulses canincrease over the time. For example, the at least one of the inter-pulsefrequency, the pulse amplitude, or the pulse width of the series ofstimulation pulses can increase linearly or exponentially over the time.In addition or alternatively the at least one of an inter-pulsefrequency, a pulse amplitude, or a pulse width of the series ofstimulation pulses can decrease over the time. For example, the at leastone of the inter-pulse frequency, the pulse amplitude, or the pulsewidth of the series of stimulation pulses can decrease linearly orexponentially over the time.

The system of any of the preceding paragraphs may also include anycombination of the following features described in this paragraph, amongothers described herein. At least one of an inter-pulse frequency, apulse amplitude, or a pulse width of the series of stimulation pulsescan increase over the time and/or a different one of the at least one atleast one of the inter-pulse frequency, the pulse amplitude, or thepulse width of the series of stimulation pulses can decrease over thetime. The time can include a first time period and a second time period.The series of stimulation pulses can be a first series of stimulationpulses over the first time period, and the stimulation waveform caninclude a second series of stimulation pulses over the second timeperiod. A pattern of the second series of stimulation pulses can match apattern of the first series of stimulation pulses. For example, thesecond series of pulses can be a copy of the first series of pulses. Thepattern of the second series of stimulation pulses can alternativelyinclude an inverted pattern of a pattern of the first series ofstimulation pulses. In some cases, the stimulation waveform can includemore than two series of pulses. The stimulation waveform can include oneor more relaxation pauses between at least some of the plurality ofpulses. The one or more processor can be further configured to adjustthe stimulation waveform based at least in part on at least one of userinput, a time of day, a user activity level, a physiological parameter,or a predetermined pattern.

A method for providing electrical stimulation to biological tissue totreat one or more medical conditions. The method can include selecting,using one or more processors, a stimulation waveform of a plurality ofstimulation waveforms that reduce an effect of neural adaption. Each ofthe plurality of stimulation waveforms can include a series ofstimulation pulses. The method can further include operating, using theone or more processors, an implantable pulse generator to deliverelectrical stimulation to biological tissue that is proximate one ormore occipital or peripheral nerves. To deliver the electricalstimulation, the one or more processors can cause the implantable pulsegenerator to apply the selected stimulation waveform via one or moreleads positioned in contact with or proximate to the biological tissue.The one or more leads can include one or more electrodes.

The method of the preceding paragraph may also include any combinationof the following features or steps described in this paragraph, amongothers described herein. At least one of an inter-pulse frequency, apulse amplitude, or a pulse width of the series of stimulation pulses ofthe selected stimulation waveform can increase or decrease over thetime. At least one of an inter-pulse frequency, a pulse amplitude, or apulse width of the series of stimulation pulses of the selectedstimulation waveform can increase over the time, while a different oneof the inter-pulse frequency, the pulse amplitude, or the pulse width ofthe series of stimulation pulses of the selected stimulation waveformcan decrease over the time.

The method of any of the preceding two paragraphs may also include anycombination of the following features or steps described in thisparagraph, among others described herein. The time can include a firsttime period and a second time period. The series of stimulation pulsescan be a first series of stimulation pulses over the first time period.The selected stimulation waveform can include a second series ofstimulation pulses over the second time period. A pattern correspondingto the first second series of stimulation pulses can match a patterncorresponding to the second series of stimulation pulses. The selectedstimulation waveform can include one or more relaxation pauses betweenat least some of the plurality of pulses. The selection is based atleast in part on at least one of a user input, a time of day, a useractivity level, a physiological parameter, or a predetermined pattern.

For purposes of summarizing the disclosure, certain aspects, advantagesand novel features are discussed herein. It is to be understood that notnecessarily all such aspects, advantages or features will be embodied inany particular embodiment of the invention and an artisan wouldrecognize from the disclosure herein a myriad of combinations of suchaspects, advantages or features.

BRIEF DESCRIPTION OF THE DRAWINGS

Embodiments of the present disclosure will now be described hereinafter,by way of example only, with reference to the accompanying drawings inwhich:

FIG. 1 illustrates an example spinal cord stimulator where theimplantable pulse generator is placed below the neck and the leads aretunneled to the occipital region.

FIG. 2 illustrates putative mechanisms of action of Occipital NerveStimulation (“ONS”) for Chronic Migraine (“CM”) & Intractable ChronicMigraine (“ICM”).

FIG. 3 illustrates a graph of firing frequency of a sensory nervedemonstrating adaptation.

FIG. 4 illustrates a graph of sensory adaptation of the cortex inresponse to a constant 4 Hz stimulation of the rat whisker²⁰.

FIG. 5 illustrates anatomy of the occipital and auricular nerves.

FIG. 6A illustrates an example diagram of a micro pulse generator andleads implanted in the occipital region.

FIG. 6B illustrates a diagram of an example Neuromodulation system.

FIG. 7 illustrates an example battery of an ONS micro pulse generator.

FIG. 8A illustrates an example processor of an ONS micro pulsegenerator.

FIG. 8B illustrates example communications between a micro pulsegenerator and a mobile device.

FIG. 9 illustrates top and side views of an example implantable pulsegenerator.

FIG. 10 illustrates an example electrical stimulation waveform for usein ONS for CM & ICM.

FIG. 11 illustrates comparative efficacy of tonic, Nevro HF10 andBurstDR waveforms for chronic pain.

FIG. 12A illustrates example graphs corresponding to Negative DecaySpike Train Stimulation.

FIG. 12B illustrates example graphs corresponding to Positive IncreaseSpike Train Stimulation.

FIGS. 13A-I illustrate example Spike Train Stimulations.

FIG. 14A illustrates an example of Positive Increase Spike TrainRepetition.

FIG. 14B illustrates an example of Negative Decay Spike TrainRepetition.

FIG. 15 illustrates an example of Spike Train Inversion.

FIG. 16 illustrates an example of Spike Train Relaxation.

FIG. 17A illustrates an example of Regular Phase Amplitude ClippingStimulation.

FIG. 17B illustrates an example of Regular Phase Width ModulatedStimulation.

FIG. 17C illustrates an example of Afferent Neuron Action PotentialFiring Frequency as Result of Increasing Pressure.

FIG. 18 illustrates example accelerometer signals displaying breathingand heartbeat information.

FIG. 19 illustrates example accelerometer signals displaying heartrate,breathing and forward motion.

FIG. 20 illustrates example waveforms for multicomponent therapeuticstimulation.

FIG. 21 illustrates example hybrid waveforms.

FIG. 22 illustrates example waveforms corresponding to independentlateral stimulation.

DETAILED DESCRIPTION

The human nervous system is vastly complex in its behavior. It ischaracterized by the electrical firing of neurons in highly organizedafferent and efferent circuits which control thought, behavior andhomeostasis. Pathological medical conditions arise when this electricalactivity becomes abnormal. Numerous therapies exist for these medicalconditions including neurostimulation therapies which utilize electricalimpulses to stimulate the nervous system in the hope of controlling oraffecting the underlying medical condition. Classically, this electricalstimulation has used static, or very simple electrical patterns.Improvements in the systems, methods and techniques for the applicationof therapeutic stimulation or modification of a patient are needed forgreater effectiveness, patient comfort and therapy durability.

Electrical stimulation of the nervous system is widely used to treatnumerous diseases such as but not limited to: Chronic Pain, Parkinson's,Essential Tremor, Urinary Incontinence, Heart Failure & Epilepsy. It isalso well recognized that the nervous system can become progressivelydesensitized to the stimulation and that beneficial therapeutic effectsmay lessen or disappear. This desensitization is thought to be theresult of the physiological phenomenon of neural adaptation.

Neural adaptation is a change over time in the responsiveness of thenervous system to a constant stimulus. It is usually experienced as achange in the perceived stimulus. For example, if one rests one's handon a table, one immediately feels the table's surface on one's skin.Within a few seconds, however, one ceases to feel the table's surface.The sensory neurons stimulated by the table's surface respondimmediately, but then respond less and less until they may not respondat all; this is an example of neural adaptation. A classic physiologyexperiment recorded the firing frequency of a sensory nerve while a limbis under constant load. As the load is applied, the initial firing rateof the sensory nerve is quite high and exceeds 120 Hz, however as timeprogresses the firing rate quickly decays to approximately 25 Hz after14 seconds (FIG. 3 ). This rapid decay in firing frequency of aperipheral sensory nerve under constant sensory input is classic neuraladaptation.

Neural adaptation is also thought to happen at a more central level suchas the cortex. Synaptic depression of thalamocortical synapses underliessensory adaptation in the cortex. FIG. 4 illustrates the sensoryadaptation of the cortex in response to a constant 4 Hz stimulation of arat whisker. The primary whisker of a rat is stimulated at 4 Hz (top ofFIG. 4 ) and the response of a cortical neuron in the correspondingregion of barrel cortex is measured with an intracellular recordingelectrode (middle of FIG. 4 ). Even though whisker stimulation ismaintained, action potentials are only evoked in the cortical cellduring the first second of stimulation. This stimulation is repeated 12times. An expanded view of the responses observed in the cortical cellduring different periods of stimulation (bottom) shows that as the trainprogresses, EPSPs became progressively smaller and eventually are nolonger able to evoke action potentials. Extensive experiments suggestthat synaptic depression at the thalamocortical synapse underlies thesensory adaptation observed during whisker stimulation.

Sensory adaptation is believed to underlie and limit the efficacy of alltherapeutic neurostimulation. Techniques aimed at overcoming adaptationwill serve to increase therapy efficacy and durability. There has beenmuch attention in the area of more efficacious stimulation for thetreatment of these neurological disorders. The current state-of-the-artis to stimulate nervous tissue in a constant manner. This disclosurediscusses introducing variability to the electrical stimulation in orderto overcome this natural neural adaptation. There has been previous artthat discloses random or non-deterministic stimulation in attempt toovercome this natural phenomenon. This disclosure discloses variable butdeterministic variability. The potential advantage of deterministicstimulation is the neuromodulation efficacy will be both repeatable anda reproducible in addition to presenting the neural tissue withvariation to overcome natural neural accommodation.

From a hardware perspective, there are no implantable devices/systemsspecifically designed for Peripheral Nerve Stimulation (“PNS”) orOccipital Nerve Stimulation (“ONS”). As mentioned before, thisdisclosure will focus on ONS for a matter of illustration. It is commonpractice to implant spinal cord stimulation (“SCS”) systems in theoccipital region for the treatment of Chronic Migraine (“CM”) &Intractable Chronic Migraine (“ICM”). The SCS devices are not approvedby the FDA for the treatment of migraines; while common, these implantsare performed off-label by the treating physician. For instance, FIG. 1illustrates a traditional spinal cord stimulator where the implantablepulse generator is placed below the neck and the leads are tunneled tothe occipital region. This is the typical off-label use of a spinal cordstimulator that is labeled for chronic pain of the trunk and/or limbs totreat various headache disorders.

Studies indicate that ONS is effective at reducing the number ofheadache days per month and improves other important metrics such asdisability and quality of life. ONS for the treatment of CM & ICM hasbeen studied in multiple clinical trials, including three randomizedclinical trials summarized in Table 1 that show a 3.1 to 18.2 reductionin headache days per month.

TABLE 1 Example Randomized Clinical Trials Reporting on ONS for CM &ICM. Publication Study Design Follow-Up Results Saper et al., 2010,Multicenter, parallel 3 months. Reduction of 8.1 (ONSTIM Study) group, N= 67. headache days per month in the ONS ancillary group vs themedically managed group. Serra & Single center, 1 month for Reduction of18.2 Marchioretto, crossover, N = 30. controlled headache days per 2012.phase. month in the ONS 12 months ON group vs. the after open medicallylabel. managed group. Silberstein et al., Multicenter, parallel 3months. Reduction of 3.1 2012, (RELIEF group with 2:1 headache days perStudy). randomization, month in the ONS N = 157. group vs the shamgroup.

The reported efficacy of ONS as a therapy of CM & ICM is superior tothat of current “gold standard” preventative treatments, such as Botoxand Topiramate. ONS also compares favorably to the recent class of drugsbeing developed by the pharmaceutical industry called CGRP antagonists,as well as recent external vagus nerve stimulators as illustrated inTable 2. This table represents the net reduction of headache days permonth after the comparable placebo or sham treatment has beensubtracted.

TABLE 2 Comparative Efficacy of ONS for CM & ICM. Headache Days perMonth Therapy Type Reduction vs Placebo/Sham Botox 1.8 Topiramate 1.7CGRP Antagonist 2.4 nVNS 1.3 ONS 3.8

The efficacy of ONS for CM & ICM is well documented in the literature.While the exact mechanism(s) of action remain unclear, there ispublished evidence that ONS affects the Trigeminal Nucleus Complex,Anterior Cingulate Cortex, Basal Ganglia, Pons, Thalamus, PeriaqueductalGrey, Cortex, Locus Cereleus, Hypothalamus and Dural Vessel Innervation.Stimulation of the Occipital Nerves modulates the Trigeminal NucleusComplex (“TNC”) by way of afferent fibers that enter the spinal cord viathe dorsal ramus of C2. Projections from the TNC to the Thalamus furthermodulate cortical circuits as well as the Hypothalamus, PeriaqueductalGrey and Locus Cereleus which further modulate the activity of the TNCvia putative descending inhibition. In parallel, ONS modulates afferentactivity to the dural vessels via the Sphenopalatine Ganglion whichreduces the release of CGRP and consequent pain processing via the V1branch of the Trigeminal Nerve as illustrated in FIG. 2 .

Despite its positive clinical efficacy, ONS is accompanied by anunacceptable level of device related adverse events. Most of theseadverse events are due to utilizing a neuromodulation system such asspinal cord stimulation (“SCS”) systems which were not designed for theoccipital region. The major adverse events reported in the three studiesare summarized in Table 3 and are mainly attributable to hardwaredeficiencies. For example, the leads from the implantable pulsegenerator (IPG) to the stimulation site must traverse the neck, a highlymobile joint, putting undue mechanical stress on the lead, causing ahigh incidence rate of lead migration. The excessive tunneling requiredto deploy the lead from the IPG to the stimulation site contributedsignificantly to the persistent pain/discomfort and the infection rates.The lack of efficacy in certain patients is also likely attributable tothe lead migration which creates ineffective stimulation of the nerve.Lastly wound site complications, skin erosion and lead breakage are alsoattributable to hardware deficiencies for this application.

TABLE 3 Adverse Events Reported from Randomized Clinical Trials on ONSfor CM & ICM. Serra & Silberstein Saper et Marchioretto et al. AdverseEvent al. (n = 51) (n = 30) (n = 157) Rate Lead migration 12 3 20 14.71%Persistent pain/discomfort at implant side 23 9.66% Infection 11 2 78.40% Lack of efficacy/benefit 8 6 5.88% Expected post-operative pain,numbness at 1 9 4.20% IPG or lead site Incision/wound site complications4 4 3.36% Undesirable changes in stimulation 7 2.94% Skin erosion 62.52% Allergic reaction to surgical materials 4 1.68% Leadbreakage/fracture 1 2 1.26% Disconnection of device 3 1.26%Nausea/vomiting 1 1 0.84% Incision site pain 2 0.84% Neck pain 2 0.84%Unintended changes in headache, 1 0.42% (severity, type or frequency)Other 14 4 7.56% TOTAL 56 5 97 66.39%

Implant Location. The tissue targeted by the electrical stimulation ofONS for CM & ICM is generally the Greater Occipital Nerve (“GON”),however there are likely therapeutic benefits to also stimulating theLesser Occipital Nerve (“LON”), Third Occipital Nerve (“TON”) andimportantly the Great Auricular Nerve (“GAN”). FIG. 5 illustrates theanatomy of the GON, LON, TON, GAN). Each nerve has a left and rightcounterpart and both must be stimulated to achieve maximum therapeuticefficacy.

In one embodiment, to deliver therapy to the occipital and auricularnerves without requiring a wire/lead to traverse the neck as illustratedin (FIG. 1 ), a micro pulse generator having a size of less than 5 cc isimplanted directly in the occipital region (FIG. 6A). From this micropulse generator, leads or wires deliver the electrical stimulationenergy to the left and right target nerves. Another potential embodimentis to implant the pulse generator just below the occiput and place theleads to the lower part of the ear. By implanting in this manner, theleads and associated electrodes would be placed over or in proximity tothe target occipital nerves. Another embodiment would be to run theleads/wires along the occipital ridge. Another potential embodimentwould be to implant the pulse generator near the submastoid process oneither side and the place the leads subcutaneous transversely across theoccipital nerve network.

Leads. There are various types of stimulation wires, or leads, which canbe used to stimulate the target tissue structures. Typical leads usedfor Spinal Cord Stimulation are percutaneous or paddle leads.Percutaneous leads are tubular in shape and have circumferentialelectrodes that stimulate omni-directionally. Paddle leads are flat inshape and have flat or surface electrodes that can stimulateuni-directionally or bi-directionally. Traditionally, percutaneous leadshave been used for ONS due to ease of placement. In addition, by usingcircumferential electrodes the stimulation energy would also stimulatethe tactile fibers of the occipital nerves potentially increasing theprobability of recruiting nervous tissue. One of the benefits of thepaddle electrodes is that they are slim and have a lower profile thanthe percutaneous leads. In addition, because the paddle leads stimulatein one direction, this type of lead may also be more energy efficient inrecruitment of the main nerve trunks such as the GON or other family ofnerves. Independent of lead type selected, it may also be beneficial tohave an anchoring mechanism on the distal end of the lead such aspolymer tines or suture holes to fasten the end of the lead to thetissue facia.

Pulse Generator. This disclosure discloses a method of determining howthe parameters that control the stimulation of biological tissue evolve.This methodology can be implemented in any pulse generator. Theconstruction of the pulse generator is not part of this disclosure butcan be well understood and can be implemented by one skilled in the art.In exemplary fashion, we illustrate the components of a standardneuromodulation system. The neuromodulation system comprises a pulsegenerator and leads which connect the pulse generator to the biologicaltissue (FIG. 6B).

Typically, a pulse generator is powered by a battery, but may be alsopowered by other means. Typically, the pulse generator is connected tothe biological tissue by one or more wires called leads. There is atleast one anode and one cathode for stimulation, but more may bepresent. In addition, electrodes located on the pulse generator itselfmay be used for stimulation, for example the metallic enclosure, or canof the device, can be used as an anode.

Typically, a pulse generator comprises several components, such as thoselisted below. The construction of a micro pulse generator small enoughto fit in the occipital region will require one skilled in the art tomake design choices that minimize the device footprint while allowingsufficient energy to provide therapeutic electrical stimulation at areasonable recharge interval of approximately 7 days. The followingsections highlight some of the major building blocks of such a micropulse generator. This serves the purpose of teaching one skilled in theart how to build such a stimulator but should not be considered limitingin any sense.

Battery (Primary Cell or Rechargeable). In order to meet the size andpower constraints of the ONS micro pulse generator, a rechargeablebattery of approximately 50 mAHr will be used. An example of such arechargeable battery is the Contego 50 mAHr battery from Eagle Picherillustrated and specified in FIG. 7 .

Microcontroller/CPU. The micro pulse generator requires a CPU to controlits operations and implement the stimulation logic and other productfeatures. There are numerous options available on the market, howeverthe recent “System on a chip” (“SoC”) has the distinct advantage ofintegrating multiple components on a single chip. The primarydeterminants of selecting such a chip are its specific capabilities,size and power consumption profile. The Nordic nRF52 family (shown inFIG. 8A) is one example of a suitable chip for the ONS application.

The nRF52 family of SoC chips has features that facilitate thedevelopment of a small volume micro pulse generator, such as:

-   -   ARM-M4 Cortex Microprocessor and FPU.    -   Flash memory and RAM.    -   Low power consumption sleep mode.    -   12 bit ADC.    -   32 bit counters/timers to implement stimulation and control        algorithms.    -   32 GPIO ports to enable external peripheral control.    -   SPI/I2C connectivity with DMA to connect the nRF52 to external        peripherals.    -   Bluetooth Low Energy Rx/Tx transceiver to communication with an        off the shelf external unit.    -   HW data encryption to enable secure data transmission.    -   NFC-A tag that allows device wakeup without BLE involvement to        save power.

Recharging Circuit. Typically custom designed to transfer energy viainductive coupling. Circuit is designed to recharge the battery quicklywhile limiting the temperature excursions of the micro pulse generator.

Antenna/Recharge Coil. Enable communication or charging of the batterywith the external instrument via a predetermined protocol. This antennamay be located inside the pulse generator, in the header where the leadsare connected, around the perimeter of the can or on the surface of thecan. One embodiment of the pulse generator is to have the communicationantenna and recharge coil as separate components. In another embodiment,the antenna and recharge coil can be tuned to serve both communicationand recharging function.

Telemetry/Communications Unit (Inductive, MICS, Bluetooth-standard,Bluetooth Low Energy (BLE), ZigBee, Wifi 802.11a/b/g/n). Enablescommunication to the external instrument, may be on-board the SoC as inthe case of the Nordic nRF52 family.

Energy Saving External Wakeup. The communication between the micro pulsegenerator and an external instrument such as an Android and/or Appletablet can occur via the Telemetry/Communications unit which can utilizea communication protocol such as Bluetooth Low Energy (BLE). Thecircuitry responsible for the communications typically consumes a largeamount of battery energy; it is therefore desirable to save energy bypowering down the communications circuitry while not in use. However,once the communications circuitry has been disabled, a mechanism isrequired to re-enable it when the external instrument/user initiates acommunication session with the micro pulse generator. While it ispossible for the micro pulse generator to periodically enable thecommunications circuitry to “poll” an external instrument, this schemewastes energy as there is very little communications between theexternal instrument and the micro pulse generator. In fact, uselesspolling may waste more energy than that which is used to communicateover time. An attractive functionality is for the external instrument tohave a means of enabling the communications circuitry in the micro pulsegenerator remotely. This can be achieved remotely by application of amagnet, or other means (such as near field communications) of triggeringa “wake-up communications” interrupt in the micro pulse generator.

The following example illustrates the use of a Near Field Communications(NFC) protocol adapted for Android and Apple devices to activate andenable the Bluetooth Low Energy (BLE) radio found in the Nordic nRF52832SoC. See also, for example, FIG. 8B.

-   -   1. User wishes to control the micro pulse generator.    -   2. User places Android or Apple device near the micro pulse        generator.    -   3. Android or Apple device initiates NFC communication to micro        pulse generator.    -   4. NFC signal is received by the NFC antenna in the micro pulse        generator. (User may now move the Android/Apple device away from        the micro pulse generator.)    -   5. Firmware on Nordic nRF52832 SoC is alerted of NFC        communication by an interrupt (Wake-Up Communications).    -   6. Firmware on the Nordic nRF52832 SoC activates the BLE radio        and functionality.    -   7. Communications occur between the Android/Apple device and the        micro pulse generator via BLE.    -   8. Once the communications session is ended by either party or a        timeout occurs, the firmware on the nRF52832 SoC shuts down the        BLE radio and functionality.    -   9. Firmware on the nRF52832 SoC resets the NFC system in order        to wait for the next wakeup from the Android/Apple device.

It is important to note that this is an example only. This power savingfeature can be implemented using a variety of protocols and hardwareconfigurations.

Output/Stimulation Unit (Charge Pump, DC-DC Converter, Switches, DCBlocking Caps). Circuitry under the control of the microprocessor andresponsible for issuing stimulation pulses to the appropriateanode-cathode pair of stimulating electrodes. May also implement somefunctionality such as impedance measurements, voltage over-headdetection, charge balancing and fault detection. The stimulationfunction could be in the configuration of an outboard circuit located onthe PCB or integrated into a microprocessor chip.

Sensing Unit (Filters, Amplifier, ADC). Responsible for the measurementof external signals, specifically physiological electrical potentials.

The neuromodulation system hardware and software described in thisdisclosure can be similar in design, construction and operation to thefollowing devices:

-   -   Cardiac stimulators such as pacemakers, ICD and CRT devices.    -   Implantable neurostimulation devices such as SCS, DBS, DRG and        PNS devices.    -   External neurostimulation devices such as TENS units and trial        therapy devices.

All of these above mentioned devices are connected to the biologicaltissue with wires called leads which may be used for stimulation (anodes& cathodes) or recording/sensing of biological activity. Furthermore,the stimulator, or pulse generator may be controlled externally by meansof another device called a “programmer” which wirelessly communicateswith the stimulation device and is able to control is behavior.

Form Factor. The form factor for the occipital implant location iscritical for comfort and durability of the implant life. Severalpreferred embodiments are listed below which may be employed to providea better fit for the micro pulse generator.

Soft Contour. The traditional material for an implantable medical deviceis Titanium. While Titanium may provide a stable hermetically sealedenvironment for the internal electronics, it is difficult to contour aTitanium case in an ergonomic manner. One embodiment would have theelectronics encased in a Titanium can and surrounded by a softermaterial such a silicone to provide soft, tapered edges which maximizecomfort and reduce associated skin tension as illustrated in FIG. 9 .This soft contour can also be used to house the recharge coil in orderto have the largest possible coil loop area for more efficient charging.Also by having the recharge coil outside and separate from the metallicenclosure helps reduce the heating and RF noise during recharging.Another embodiment is to encase the internal electronics in epoxy, glassor ceramics.

Electric Stimulation/Waveform. The electrical stimulation waveformgenerally used in ONS for CM & ICM is a traditional “Tonic” waveformwhich uses a repeating pattern of square pulses as illustrated in FIG.10 . This stimulation pattern is characterized by pulse amplitude, pulsewidth and stimulation frequency which are fixed parameters and do notevolve over time.

In recent years, newer advanced waveforms for SCS systems have beendeveloped for the treatment of Chronic Pain. These waveforms can differsignificantly from the tonic waveform and have demonstrated an increasein efficacy of pain relief as well as emotional and psychologicalbenefits. The waveforms are described in greater detail in U.S. Pub. No.2011/0184488 (hereinafter “Nevro”), entitled SPINAL CORD STIMULATION TOTREAT PAIN, and U.S. Pub. No. 2012/0016437 (hereinafter “BurstDR”),entitled SELECTIVE HIGH FREQUENCY SPINAL CORD MODULATION FOR INHIBITINGPAIN WITH REDUCED SIDE EFFECTS, AND ASSOCIATED SYSTEMS AND METHODS, eachof which is hereby incorporated by reference herein in its entirety.

In clinical studies, both advanced waveforms (for example, thosedescribed in Nevro, BurstDR) reduced the amplitude of the chronic painin patients when compared to Tonic stimulation. This reduction in painis evidenced by the reduction in VAS score which is a common painassessment metric. It is noteworthy that Tonic stimulation significantlyreduced VAS pain scores compared to Baseline and is considered aneffective therapy, however, the advanced waveforms further reduced theVAS scores by approximately 49% compared to Tonic. In addition to thereduction of the VAS pain score, the BurstDR stimulation waveform alsoimproved psychological metrics such as the Pain Catastrophizing Scale(“PCS”) and the McGill Sensory and Affective scales indicating that theimprovement associated with the advanced waveform provides benefits tothe patient in multiple dimensions (FIG. 11 ).

The above referenced waveforms serve to illustrate the importance of thestimulation waveform in the ultimate efficacy of therapy. It is believedby the inventors and authors of this application that the efficacy ofONS for CM & ICM can be significantly increased by a waveform designedto counteract the phenomenon of adaptation as described earlier.

There are multiple parameters that control electrical stimulation ofbiologic tissue, such as, but not limited to, Amplitude, Pulse width,Frequency, Electrode configuration, Electrode polarity, Stimulationcycling with various on and off times, Recharge characteristics such asactive/passive, and/or Pulse shape such as square or triangular(sloped).

Embodiments of the present disclosure provide systems and methods ofmodifying the stimulation waveform and parameters to increase thetherapy efficacy and long term durability of ONS for CM & ICM (hereafterreferred to as the “Waveforms”). These Waveforms may be usedindependently or in conjunction with one another. Additionally, they maybe used at different times or under different conditions.

Embodiments of the present disclosure provide systems and methods of usefor providing multiple Waveforms that may result in different benefitsto the patient depending on the clinical context. It is thereforeconceivable that certain Waveforms may be used in certain conditions andother Waveforms used in differing conditions. The implantable micropulse generator may have the ability to change the Waveformautomatically or by virtue of a command from the physician or patient.Depending on the physiological context which may be asserted by variousmeans such as measuring a physiological parameter (nerve activity, bloodpressure, etc.), one or more parameters of the Waveform may be changed.This change may also be performed for other reasons, such as but notlimited to user input, time of day, periodicity, user activity level, aphysiological parameter, or defined period of time.

WAVEFORMS. Embodiments of the present disclosure provide systems andmethods for providing several novel waveforms detailed below. Thesewaveforms may be used independently or in conjunction to one another.

-   -   Negative Decay Spike Train Stimulation.    -   Positive Increase Spike Train Stimulation.    -   Spike Train Repetition.    -   Spike Train Inversion.    -   Spike Train Relaxation.    -   Force Modulated Stimulation.    -   Multi-component Therapeutic Stimulation.

SPIKE TRAIN ADAPTATION. Considering the physiology and associatedphenomenon illustrated in FIG. 3 and FIG. 4 where the firing frequencyin sensory nerves naturally decays over time in spite of constantsensory stimulation, there are several “Spike Train Adaptation”inventions that could be beneficial for long-term efficacy ofneurostimulation therapies.

NEGATIVE DECAY SPIKE TRAIN STIMULATION. In this waveform modality, theinter-pulse frequency decays in a manner similar to the naturaladaptation of sensory nerves. The premise is that a stimulation profilemimicking a natural firing pattern will not lead to central or corticaladaptation (FIG. 12A).

POSITIVE INCREASE SPIKE TRAIN STIMULATION. In this waveform modality,the inter-pulse frequency increases in a manner that is opposite to thenatural adaptation of sensory nerves. The premise is that issuingstimulation pulses in at an increasing rate will overcome the naturaltendency to adapt to the stimulation and thus increase therapeuticefficacy (FIG. 12B).

The previous embodiments describe Spike Train Stimulation relative togrowth (increasing) or decay (decreasing) of the frequency in a linearfashion. Another embodiment of the Spike Train Stimulation is to have awaveform that grows or decays over time in a ramping fashion for otherstimulation parameters such as amplitude or pulse width. FIG. 13A showsdecaying pulse width in a linear fashion. FIG. 13B shows growing pulsewidth in a linear fashion. FIG. 13C shows alternating decaying andgrowing pulse width waveforms.

Similarly, the waveform can grow or decay over time in a ramping fashionwhere amplitude is the only variable parameter. FIG. 13D shows decayingamplitude, FIG. 13E shows growing amplitude and FIG. 13F shows decayingand growing amplitude in alternating fashion.

These parameters can be isolated to only parameter change as describedabove or they could be combined to create more complex signals. FIG. 13Gillustrates a waveform with decaying pulse width and amplitude. FIG. 13Hshows a waveform with a decaying amplitude and a growing pulse width.FIG. 13I shows a waveform with a growing frequency and decaying pulsewidth. There are many different combinations that can be created and allwill not be detailed here.

SPIKE TRAIN REPETITION. As can be observed in FIG. 3 & FIG. 4 ,significant adaptation can occur in a matter of seconds. Therefore, thespike trains can have durations of approximately half a second to aminute (0.5 sec-60 sec). Once a spike train has completed, a new spiketrain is issued in a repetitive manner. One embodiment of the disclosureto overcome the adaption phenomenon is to stimulate the tissue with apositive increase spike train in repetitive fashion as illustrated inFIG. 14A. Another embodiment of the disclosure is to stimulate thetissue with a negative-decaying spike train in repetitive fashion asshown in FIG. 14B.

SPIKE TRAIN INVERSION. In some instances, it may be desirable to invertthe successive spike trains from positive to negative and vice-versa asillustrated in FIG. 15 .

SPIKE TRAIN RELAXATION. As the spike trains will progressively activatethe nerve and potentially trigger adaptation mechanisms, it may bedesirable to add relaxation pauses between some of the spike trains.During these pauses, no stimulation pulses will be issued and theduration of the pauses will range approximately from 1 ms-60 seconds asshown in FIG. 16 .

REGULARITY. It is noteworthy that the spike train waveforms are regularand deterministic in nature. There is no randomness or irregularity ofthe waveform.

REGULAR PHASE AMPLITUDE CLIPPING STIMULATION. In this waveform modality,a constant amplitude stimulation waveform is amplitude modulated by aregular, predetermine function such a Y=Sin(X) which is superimposed onthe stimulation waveform and serves to determine the amplitude at eachstimulation pulse (FIG. 17A).

REGULAR PHASE WIDTH MODULATED STIMULATION. In this waveform modality, aconstant amplitude stimulation waveform is width modulated by a regular,predetermine function such a Y=Sin(X) which is superimposed on thestimulation waveform and serves to determine the pulse width at eachstimulation pulse (FIG. 17C).

FORCE MODULATED STIMULATION. The human body is continually exposed tomechanical forces such as motion, pressure, breathing, and heart beats.These forces are received by sensory nerves and their rate of firingconstantly changes in response to the changing forces. FIG. 17Cillustrates the increase in firing frequency of action potentials in asensory afferent neuron in response to increase probe pressures on theskin. This phenomenon is experienced across the entire body and minutechanges in posture, breathing, neck movement, all cause perpetualchanges in the action potential firing frequency of afferent sensoryneurons.

The mechanical forces to which the body is continually subject to,whether large or small, can be measured using an apparatus called an“accelerometer”. The accelerometer is a relatively small electroniccomponent which translates forces in one or multiples axis intoelectrical signals. The raw data from the accelerometer is thencaptured, read and processed by a microprocessor or a Digital SignalProcessor (DSP). Accelerometers are widely used today to detect bodyposition, activity, heartbeat and respiration rate. FIG. 18 illustratesthe signal collected from the Z axis of an accelerometer placed on thechest of an individual. There are two major visible components in thatsignal. The “spikes” correlate to actual heartbeats, which is evidencedby the fact that they occur at the same time as the QRS complexes in theECG. The slower sinusoidal drift of the baseline represents the motionof the chest in response to breathing. In this example, the X & Y axisdata is not illustrated.

FIG. 19 illustrates a scenario where the accelerometer is placed on anindividual's chest. The raw signal from the analog accelerometer isamplified, filtered and sampled via an analog to digital converter(“ADC”) such as the one found on the Nordic nRF52 family chips. Note,certain accelerometers have the ADC embedded and therefore cancommunicate digitized signals; these are termed digital accelerometers.The sampled values are then processed by a DSP and physiologicalinformation such as heart rate, respiration and motion are extractedfrom signal.

It is customary to heavily filter and process the raw accelerometersignal in order to extract the signal of interest such as heartrate.However, in removing all of the other unwanted parts of the signal, onealso removes minute but physiologically relevant information. Theseminute variations in the raw signal represent minute variations inforces to which the body is exposed and to which the nervous systemresponds by modulating the afferent firing frequency of sensory nerves.One embodiment of the present disclosure describes a method of usingthese unwanted or left over signals of the accelerometer signal tomodulate the electrical stimulation pattern of the micro pulse generatorfor electrical stimulation therapy. More specifically, these left oversignals could be used for ONS therapy to treat conditions such as CM &ICM by stimulating the target nerves which may perceive them as anaturally variable signal. These signals that are typically left overfrom the traditional use of an accelerometer can be used to either bethe primary driver of the therapeutic stimulation or used to wobblearound an already know therapeutic stimulation.

One embodiment of the present disclosure presents a method to capturethe above described left over signals by considering a raw accelerometersignal where each axis is sampled in a 32 bit sample. The leastsignificant bits (“LSB”) of this sample represent minute variations inforce and may be used to modulate the parameters of stimulation. It isadditionally possible that multiple stimulation parameters may bemodulated by different bit patterns in the sample. Yet anotherembodiment can utilize the LSBs of different accelerometer axis samplesto modulate multiple stimulation parameters. The axis samples may alsobe mathematically combined to modulate one or more stimulationparameters.

EXAMPLE Accelerometer Modulated Stimulation Frequency

In another embodiment a pulse generator is programmed to deliverstimulation at a certain Base Frequency (F), Amplitude (A) and PulseWidth (PW) that contains a 3-axis digital accelerometer which producesunfiltered 32 bit samples for each axis at every sampling period. Thepulse generator algorithm will sample the accelerometer X axis(X_SAMPLE) value at every stimulation pulse; once the current pulse isissued with (A, PW), a timer is set to determine the time for the nextpulse. In tonic stimulation, this timer would be set to 1/F (theperiod). However, in one embodiment we set the timer value to:Timer=(1/F)+(−2³+X_SAMPLE[0..3]) where the timer value (period) will bebetween [1/F−8, 1/F+8] since we used the 4 least significant bits (LSB)of the X sample (bit0..bit3). As previously discussed, the leastsignificant bits of the raw unfiltered accelerometer sample containminute but physiologically relevant information. In the above example,we extracted the 4 LSB's and used that value to modulate the stimulationfrequency. The amplitude of the oscillation in frequency is bound from 0to 2⁴ as no scaling factor was applied. The central frequency is thephysician programmed base frequency (F). For example, if the physicianprogrammed F=60 Hz, then at every pulse the accelerometer LSB's wouldcause the effective stimulation frequency to be between 52 Hz (60−2³)and 68 Hz (60+2³). This oscillation in frequency is providing aphysiologically natural signal to the nervous system since afferentsensory fibers constantly change their firing frequency in response tominute changes in forces applied to the body.

There are numerous possible embodiments of this disclosure. Thefollowing possible embodiments are listed as examples and not meant tobe limiting. Each example will be written in pseudo code that should beunderstood by one skilled in the art. The following information isuseful to understanding the pseudocode:

-   -   Function IssuePulse is called by the pulse generator firmware        every time a pulse is to be issued. The call to this function        can be made from different locations in the IPG firmware,        however it is common for this function to be called directly        from the service routine of a hardware timer used to control the        stimulation. The hardware timer will assert an interrupt at        every (1/Frequency) time period.    -   ProgAmp is the base amplitude for stimulation programmed by the        physician.    -   ProgPW is the base pulse width for stimulation programmed by the        physician.    -   ProgElectrodes contains the information related to the selected        electrodes to be used for stimulation by the physician. This may        be an array of numbers indicating for each electrode whether it        is OFF, ANODE or CATHODE.    -   Function SampleAccel retrieves a force sample from the        accelerometer. This is a raw sample that is not filtered,        averaged or modified in any way. This value may come directly        from a digital accelerometer or from an ADC sampling an analog        accelerometer. The argument passed to this function represents        which axis of the accelerometer is to be sampled.    -   Function OutputPulse is used to cause a stimulation pulse to be        issued by the output circuitry. For simplicity, we pass this        function all of the necessary arguments required to issue this        pulse: Amplitude, Pulse Width, and Electrode Configuration.    -   FreqDelta is a variable that will be used to control the        frequency of the subsequent pulses. If this variable is set to        zero, then the timers will be set according to the programmed        frequency by the physician (ProgFreq). Otherwise the timers will        be set according to ProgFreq+FreqDelta.    -   The X[0..3] notation in this pseudo-code indicates that the        operation is to use the 4 least significant bits of X. The        square brackets [ ] will be used for the purposed of extracting        a set of contiguous bits from a larger word. Assume that X is a        32 bit unsigned integer, the ANSI C equivalent to A=X[0..3]        would be:    -   A=X & 0x0000000F;

Here are several embodiments of various stimulation output routineswritten to utilize the data from the accelerometer in a way to modulatethe output pulse:

Embodiment 1—Four LSBs from the X Axis of Accelerometer are Added“Wobble” to the Amplitude Output

Function IssuePulse (void) { X = SampleAccel(X_AXIS); Amp = ProgrAmp +X[0..3]; OutputPulse (Amp, ProgPW, ProgElectrodes); }

Embodiment 2—Four LSBs from X Axis of Accelerometer are Added “Wobble”to the Amplitude Output and Four LSBs from the Y Axis are Added “Wobble”to the Pulse Width Output

Function IssuePulse { X = SampleAccel(X_AXIS); Y = SampleAccel(Y_AXIS);Amp = ProgrAmp + X[0..3]; PW = ProgPW − Y[0..1]; OutputPulse (Amp, PW,ProgElectrodes); }

Embodiment 3—Three LSBs from the X Axis and Three LSBs from the Z Axisof Accelerometer are Added “Wobble” to the Amplitude Output and Two LSBsfrom the Y Axis are Added “Wobble” to the Pulse Width Output

Function IssuePulse (void) { X = SampleAccel(X_AXIS); Y =SampleAccel(Y_AXIS); Z = SampleAccel(Z_AXIS); Amp = ProgrAmp + X[0..2] +Z[0..2} << 2; PW = ProgPW − Y[0..1]; OutputPulse (Amp, PW,ProgElectrodes); }

Similarly, the “left over” signal from the accelerometer can be used tomodulate other stimulation parameters such as Amplitude (Amp), PulseWidth (PW) and Frequency Delta (FreqDelta). These parameters aremodified by using transform functions such as TransformAmp whichimplement any mathematical expression. The results of this transform arethen scaled according to an arbitrary scaling factor. Finally, thescaled transformed values are range checked to make sure they are stillwithin the bounds of safety and device performance envelope.

Embodiment 4—Sample Data Received from the Accelerometer is Used toTransform the Amplitude, Pulse Width and Frequency Based on a DesiredTransform Mathematical Expression. In Addition, a Scaling Factor can beAdded to Adjust the Impact of Modulation

Function IssuePulse(void) { X = SampleAccel(X_AXIS); Y =SampleAccel(Y_AXIS); Z = SampleAccel(Z_AXIS); Amp =TransfromAmp(ProgrAmp , X) * ScalingFactorAmp; PW = TransfromPW(ProgrPW, Y) * ScalingFactorPW; FreqDelta = TransfromFreq(ProgFreq, , Z) *ScalingFactorFreq; RangeCheck (Amp, PW, FreqDelta); OutputPulse (Amp,PW, ProgElectrodes); }

The above described functions are example embodiments of the presentdisclosure. It is also conceivable that other physiological metricsbeyond motion such as EEG, ECG, Heart Rate Variability and naturalsignals such as sound, ambient temperature, atmospheric pressure couldbe used as an input signal to drive the modulation described above. Forinstance, the sample data from an EEG signal could be used in lieu ofthe sample data used from the accelerometer in the above example.

Similarly, there are synthetic signals such as music or harmonic soundsthat could be used to primarily drive and/or complement therapeuticstimulation similar to the physiological or natural signals. Forexample, one embodiment could be using music as an input variable todetermine the baseline parameter set, to provide the “wobble” in theprimary stimulation parameter set or the mask to clip the desiredwaveform. A user could select their favorite song from their personalcontroller or inform the physician of their selection.

MULTICOMPONENT THERAPEUTIC STIMULATION. It is well known that thestimulation parameters used in ONS for CM & ICM affect the sensationperceived by the patient as well as the efficacy of therapy. Oneembodiment describes a method of combining stimulation parameters orWaveforms in order to combine the benefits of each individual parametercombination.

Assume a parameter set for ONS known to be efficacious at reducingheadache frequency in a specific patient; for example Frequency 60 Hz,Amplitude 2 milli Amps and pulse width 450 micro seconds, let's callthis Waveform1 in this example. Also assume a second waveform in thesame patient which produces a pleasant massaging sensation, Frequency 11Hz, Amplitude 0.5 milliAmps and pulse width of 750 micro seconds, let'scall this Waveform 2 in this example. This disclosure proposes tosuperimpose both stimulation waveforms on the same stimulation channelsimultaneously to provide both the therapeutic efficacy and pleasantmassaging sensation to the patient. In isolation, the waveforms looklike FIG. 20 .

In order to provide the patient with the benefit of both waveforms, theywill be superimposed by the micro pulse generator output circuitry andthe patient will be stimulated with a hybrid waveform which is the sumof Waveform1 and Waveform2; this hybrid waveform will look similar toFIG. 21 .

It is also expected that certain constraints may exist in the outputcircuitry of the micro pulse generator which may require some slightadjustments to the waveform in order to avoid pulse collisions,ineffective charge balancing and other technical considerations. Theseconstraints will depend on the individual hardware however they are allanticipated in this disclosure. All of the parameters previouslydescribed in this disclosure can be modified for the purposes of meetinghardware constrains.

LATERAL COMPARTIMENTALIZATION. Therapeutic stimulation of the OccipitalNerves for headache disorders such as CM and ICM, the same frequency istraditionally used on both the left and right occipital nerve network.There exists much asymmetry in the human body as well as in thepresentation of CM & ICM in terms of the laterality of pain and shiftingof pain patterns. In order to realize the maximum benefit of therapy,all parameters controlling stimulation should be independent between theleft and right side stimulation because as the pain pattern shift so maythe necessary therapeutic stimulation to provide efficacy.

INDEPENDENT LATERAL STIMULATION. ONS therapy for CM and ICM generallyrequires stimulation of the left and right occipital nerves. Aspreviously described, an embodiment described in this disclosure is tohave fully independent parameters sets for the left and right sidedstimulation such as both sides can be independently optimized. In afirst embodiment, the stimulation patterns on the left and rightoccipital nerves are occurring simultaneously. However, this may lead tohigh level habituation by the thalamus and may render therapy lesseffective over time. In order to defeat this habituation, the left andright sided stimulation may be alternated, such that the left side isbeing stimulated for a few seconds (Left Train) while the right side isquiescent; at the end of that stimulation period, the right side isstimulated (Right Train) while the left side is quiescent. This lateralalternation will cause a wobbling effect in the Thalamus preventingaccommodation and habituation. In another embodiment there is an overlapbetween the left and right stimulation such that a blended effect willoccur. In yet another embodiment, the left and right sided repeatfrequencies are different such that their occurrence relative to oneanother or phase changes with time, further preventing accommodation andhabituation (FIG. 23 ).

The concepts described in this application are compatible with and canbe used in conjunction with any combination of the embodiments and/orfeatures described in the following publications: (1) Carl Haub andToshiko Kaneda, 2013 World Population Data Sheet; (2) Carod-Artal,Francisco Javier. “Tackling Chronic Migraine: Current Perspectives.”Journal of Pain Research 7 (2014): 185-94. doi:10.2147/JPR.S61819; (3)Schramm, Sara H., Mark Obermann, Zaza Katsarava, Hans-Christoph Diener,Susanne Moebus, and Min-Suk Yoon. “Epidemiological Profiles of Patientswith Chronic Migraine and Chronic Tension-Type Headache.” The Journal ofHeadache and Pain 14 (May 7, 2013): 40. doi:10.1186/1129-2377-14-40; (4)Latinovic, R. “Headache and Migraine in Primary Care: Consultation,Prescription, and Referral Rates in a Large Population.” Journal ofNeurology, Neurosurgery & Psychiatry 77, no. 3 (Jul. 26, 2005): 385-87.doi:10.1136/jnnp.2005.073221. (5) https://migraineresearchfoundation.org/about-migraine/migraine-facts; (6)Headache Classification Committee of the International Headache Society(IHS). “The International Classification of Headache Disorders, 3rdEdition (Beta Version).” Cephalalgia 33, no. 9 (Jul. 1, 2013): 629-808.doi:10.1177/0333102413485658; (7) Menken, M., T. L. Munsat, and J. F.Toole. “The Global Burden of Disease Study: Implications for Neurology.”Archives of Neurology 57, no. 3 (March 2000): 418-20; (8) Matharu,Manjit S. “BOTOX®(Botulinum Toxin Type A, BoNTA, Allergan) in theManagement of Chronic Migraine.” Accessed Oct. 1, 2016.http://www.clusterheadacheinfo.org/local--files/file:botox-allergan/Botox_Allergan.pdf;(9) Silberstein, Stephen D., Richard B. Lipton, David W. Dodick,Frederick G. Freitag, Nabih Ramadan, Ninan Mathew, Jan L. Brandes, etal. “Efficacy and Safety of Topiramate for the Treatment of ChronicMigraine: A Randomized, Double-Blind, Placebo-Controlled Trial.”Headache: The Journal of Head and Face Pain 47, no. 2 (February 2007):170-80. doi:10.1111/j.1526-4610.2006.00684.x; (10) Portfolio, Product,Access To Healthcare, Stay Up-to-Date, and Financial Data. “NovartisAnnounces AMG 334 Significantly Reduces Patients' Monthly Migraine Daysin Phase II Study of Chronic Migraine Prevention.” Accessed Oct. 2,2016.https://www.novartis.com/news/media-releases/novartis-announces-amg-334-significantly-reduces-patients-monthly-migraine-days;(11) Silberstein, Stephen D., Anne H. Calhoun, Richard B. Lipton, BrianM. Grosberg, Roger K. Cady, Stefanie Dorlas, Kristy A. Simmons, et al.“Chronic Migraine Headache Prevention with Noninvasive Vagus NerveStimulation: The EVENT Study.” Neurology 87, no. 5 (Aug. 2, 2016):529-38. doi:10.1212/WNL.0000000000002918; (12) Dodick, D. W., S. D.Silberstein, K. L. Reed, T. R. Deer, K. V. Slavin, B. Huh, A. D. Sharan,et al. “Safety and Efficacy of Peripheral Nerve Stimulation of theOccipital Nerves for the Management of Chronic Migraine: Long-TermResults from a Randomized, Multicenter, Double-Blinded, ControlledStudy.” Cephalalgia 35, no. 4 (Apr. 1, 2015): 344-58.doi:10.1177/0333102414543331; (13) Saper, Joel R., David W. Dodick,Stephen D. Silberstein, Sally McCarville, Mark Sun, and Peter J.Goadsby. “Occipital Nerve Stimulation for the Treatment of IntractableChronic Migraine Headache: ONSTIM Feasibility Study.” Cephalalgia : AnInternational Journal of Headache 31, no. 3 (February 2011): 271-85.doi:10.1177/0333102410381142; (14) Miller, Sarah, Alex J. Sinclair,Brendan Davies, and Manjit Matharu. “Neurostimulation in the Treatmentof Primary Headaches.” Practical Neurology, 2016, practneurol-2015; (15)Bartsch, Goadsby & al. “Stimulation of the Greater Occipital NerveInduces Increased Central Excitability of Dural Afferent Input.” Brain125, no. 7 (Jul. 1, 2002): 1496; (16) Magis, Jean Schoenen & al.“Central Modulation in Cluster Headache Patients Treated with OccipitalNerve Stimulation: An FDG-PET Study.” BMC Neurology 11, no. 1 (2011): 1;(17) Matharu.“Central Neuromodulation in Chronic Migraine Patients withSuboccipital Stimulators: A PET Study.” Brain 127, no. 1 (Jan. 1, 2004):220-30. doi:10.1093/brain/awh022; (18) Vincent & al. Ottar Sjaastad.“Reduction of Calcitonin Gene-Related Peptide in Jugular Blood FollowingElectrical Stimulation of Rat Greater Occipital Nerve.” Cephalalgia 12,no. 5 (1992); (19) Abbott, Regehr, “Synaptic Computation”, Nature. 2004October 14; 431(7010):796-803; and/or (20) Matthews, B. H. C. 1931. Theresponse of a single end organ. Journal of Physiology, 71, 64-110. Eachof these publications is expressly bodily incorporated in its entiretyand is part of this disclosure. Some or all of the features describedherein can be used or otherwise combined together or with any of thefeatures described in these publications.

APPLICABILITY AND GENERALIZATION OF INVENTIONS. This applicationpresents examples in the context of ONS therapy for CM & ICM; this ismeant to be illustrative and not limiting. The concepts of accommodationand habituation are omnipresent in all nervous tissue of the human bodyand non-nervous tissue as well. Thus, the described systems and methodare applicable to a wide range of neurological disorders. For example,other applications can include, but are not limited to: Spinal CordStimulation for Chronic Pain, Deep Brain Stimulation for MovementDisorders, Vagus Nerve Stimulation for Epilepsy, Obesity andInflammation, Tibial Nerve Stimulation for Incontinence, PancreaticStimulation for Diabetes, Cortical Stimulation for Epilepsy and PostStroke Rehabilitation, Visceral Organ stimulation, Vascular stimulation,Muscle stimulation, and/or Other biological tissue responsive to theforms of stimulation listed below.

In addition, the stimulation profiles described within can be applied tomany other means beyond electrical stimulation such as mechanical,ultrasonic, thermal, light, magnetic and electro-magnetic stimulation toevoke potentials in tissue.

Similarly, the hardware disclosures described in this application arerelated to an implantable pulse generator however it is conceivablethese inventions could apply to devices that provide powertranscutaneously to an implanted transceiver or that provide energy tothe nerve structure entirely transcutaneously.

While certain embodiments of the inventions have been described, theseembodiments have been presented by way of example only, and are notintended to limit the scope of the disclosure. Indeed, the novel methodsand systems described herein may be embodied in a variety of otherforms. Furthermore, various omissions, substitutions and changes in thesystems and methods described herein may be made without departing fromthe spirit of the disclosure. Additionally, aspects, components,methods, features, advantages, and embodiments described herein can becombined with aspects, components, methods, features, advantages, andembodiments described in the publications and applications incorporatedby reference here in.

Features, materials, characteristics, or groups described in conjunctionwith a particular aspect, embodiment, or example are to be understood tobe applicable to any other aspect, embodiment or example described inthis section or elsewhere in this specification unless incompatibletherewith. All of the features disclosed in this specification(including any accompanying claims, abstract and drawings), and/or allof the steps of any method or process so disclosed, may be combined inany combination, except combinations where at least some of suchfeatures and/or steps are mutually exclusive. The protection is notrestricted to the details of any foregoing embodiments. The protectionextends to any novel one, or any novel combination, of the featuresdisclosed in this specification (including any accompanying claims,abstract and drawings), or to any novel one, or any novel combination,of the steps of any method or process so disclosed.

Furthermore, certain features that are described in this disclosure inthe context of separate implementations can also be implemented incombination in a single implementation. Conversely, various featuresthat are described in the context of a single implementation can also beimplemented in multiple implementations separately or in any suitablesubcombination. Moreover, although features may be described above asacting in certain combinations, one or more features from a claimedcombination can, in some cases, be excised from the combination, and thecombination may be claimed as a subcombination or variation of asubcombination.

Moreover, while operations may be depicted in the drawings or describedin the specification in a particular order, such operations need not beperformed in the particular order shown or in sequential order, or thatall operations be performed, to achieve desirable results. Otheroperations that are not depicted or described can be incorporated in theexample methods and processes. For example, one or more additionaloperations can be performed before, after, simultaneously, or betweenany of the described operations. Further, the operations may berearranged or reordered in other implementations. Those skilled in theart will appreciate that in some embodiments, the actual steps taken inthe processes illustrated and/or disclosed may differ from those shownin the figures. Depending on the embodiment, certain of the stepsdescribed above may be removed, others may be added. Furthermore, thefeatures and attributes of the specific embodiments disclosed above maybe combined in different ways to form additional embodiments, all ofwhich fall within the scope of the present disclosure. Also, theseparation of various system components in the implementations describedabove should not be understood as requiring such separation in allimplementations, and it should be understood that the describedcomponents and systems can generally be integrated together in a singleproduct or packaged into multiple products.

For purposes of this disclosure, certain aspects, advantages, and novelfeatures are described herein. Not necessarily all such advantages maybe achieved in accordance with any particular embodiment. Thus, forexample, those skilled in the art will recognize that the disclosure maybe embodied or carried out in a manner that achieves one advantage or agroup of advantages as taught herein without necessarily achieving otheradvantages as may be taught or suggested herein.

Conditional language, such as “can,” “could,” “might,” or “may,” unlessspecifically stated otherwise, or otherwise understood within thecontext as used, is generally intended to convey that certainembodiments include, while other embodiments do not include, certainfeatures, elements, and/or steps. Thus, such conditional language is notgenerally intended to imply that features, elements, and/or steps are inany way required for one or more embodiments or that one or moreembodiments necessarily include logic for deciding, with or without userinput or prompting, whether these features, elements, and/or steps areincluded or are to be performed in any particular embodiment.

Conjunctive language such as the phrase “at least one of X, Y, and Z,”unless specifically stated otherwise, is otherwise understood with thecontext as used in general to convey that an item, term, etc. may beeither X, Y, or Z. Thus, such conjunctive language is not generallyintended to imply that certain embodiments require the presence of atleast one of X, at least one of Y, and at least one of Z.

Language of degree used herein, such as the terms “approximately,”“about,” “generally,” and “substantially” as used herein represent avalue, amount, or characteristic close to the stated value, amount, orcharacteristic that still performs a desired function or achieves adesired result. For example, the terms “approximately”, “about”,“generally,” and “substantially” may refer to an amount that is withinless than 10% of, within less than 5% of, within less than 1% of, withinless than 0.1% of, and within less than 0.01% of the stated amount. Asanother example, in certain embodiments, the terms “generally parallel”and “substantially parallel” refer to a value, amount, or characteristicthat departs from exactly parallel by less than or equal to 15 degrees,10 degrees, 5 degrees, 3 degrees, 1 degree, or 0.1 degree.

The scope of the present disclosure is not intended to be limited by thespecific disclosures of preferred embodiments in this section orelsewhere in this specification, and may be defined by claims aspresented in this section or elsewhere in this specification or aspresented in the future. The language of the claims is to be interpretedbroadly based on the language employed in the claims and not limited tothe examples described in the present specification or during theprosecution of the application, which examples are to be construed asnon-exclusive.

What is claimed is:
 1. A system for providing electrical stimulation tobiological tissue to treat one or more medical conditions comprising:one or more leads configured to be positioned in contact with orproximate to biological tissue that is proximate one or more occipitalor peripheral nerves; an implantable pulse generator configured todeliver electrical stimulation to the biological tissue via the one ormore leads; a power source configured to operatively connect and supplypower to the implantable pulse generator; a motion sensor positionedproximate to a body of a patient and configured to generate a rawpatient signal; and one or more processors configured to: receive theraw patient signal from the motion sensor; identify major variations andminor variations in the raw patient signal, wherein the major variationsand minor variations correspond to one or more forces to which the bodyis exposed, wherein the major variations correspond to a signal ofinterest portion including physiologically significant information fromthe raw patient signal, and wherein the minor variations correspond tominute physiologically least significant information of an unwanted orleft over signal portion of the raw patient signal; periodically captureand extract insignificant data from minor variations that correspond tominute physiologically least significant information of the unwanted orleft over signal portion of the raw patient signal unrelated tophysiologically significant major variations of the signal of interestportion, wherein the insignificant data is limited to being extractedfrom portions corresponding to the minor variations, wherein theinsignificant data is used to generate a stimulation signal by tuning astimulation waveform according to the minor variations in the rawpatient signal such that the stimulation waveform is adapted to reducean effect of neural accommodation or adaptation, and wherein the use ofthe insignificant data is unrelated to tailoring the stimulation basedon the sensed physiologically significant major variations in the rawpatient signal toward a predefined profile, wherein the stimulationwaveform comprises a series of rectangular pulses that vary in pulsewidth over time; and cause the implantable pulse generator to deliverthe electrical stimulation via the stimulation signal.
 2. The system ofclaim 1, wherein at least one of an inter-pulse frequency, a pulseamplitude, or the pulse width of the series of rectangular pulsesincreases over the time.
 3. The system of claim 2, wherein the at leastone of the inter-pulse frequency, the pulse amplitude, or the pulsewidth of the series of rectangular pulses increases linearly over thetime.
 4. The system of claim 2, wherein the at least one of theinter-pulse frequency, the pulse amplitude, or the pulse width of theseries of rectangular pulses increases exponentially over the time. 5.The system of claim 1, wherein at least one of an inter-pulse frequency,a pulse amplitude, or the pulse width of the series of rectangularpulses decreases over the time.
 6. The system of claim 5, wherein the atleast one of the inter-pulse frequency, the pulse amplitude, or thepulse width of the series of rectangular pulses decreases linearly overthe time.
 7. The system of claim 5, wherein the at least one of theinter-pulse frequency, the pulse amplitude, or the pulse width of theseries of rectangular pulses decreases exponentially over the time. 8.The system of claim 1, wherein at least one of an inter-pulse frequency,a pulse amplitude, or the pulse width of the series of rectangularpulses increases over the time, and wherein a different one of the atleast one of the inter-pulse frequency, the pulse amplitude, or thepulse width of the series of rectangular pulses decreases over the time.9. The system of claim 1, wherein the series of rectangular pulses is afirst series of rectangular pulses over a first time period, and whereinthe stimulation waveform comprises a second series of rectangular pulsesover a second time period.
 10. The system of claim 9, wherein a patternof the second series of rectangular pulses matches a pattern of thefirst series of rectangular pulses.
 11. The system of claim 9, wherein apattern of the second series of rectangular pulses comprises an invertedpattern of a pattern of the first series of rectangular pulses.
 12. Thesystem of claim 9, wherein the motion sensor is an accelerometer,wherein the stimulation waveform is characterized by a base frequency,amplitude, and pulse width, wherein tuning the stimulation waveformcomprises modulating at least one of the base frequency, amplitude, orpulse width based on the minor variations in the raw patient signal. 13.The system of claim 1, wherein the one or more processors is furtherconfigured to further tune the stimulation signal based at least in parton at least one of user input, a time of day, a user activity level, aphysiological parameter, or a predetermined pattern.
 14. The system ofclaim 1, wherein an inter-pulse frequency of the series of rectangularpulses varies over the time.
 15. The system of claim 1, wherein anamplitude of the series of rectangular pulses varies over the time. 16.A method for providing electrical stimulation to biological tissue totreat medical conditions, the method comprising: receiving a raw patientsignal from a motion sensor, wherein the motion sensor is positionedproximate to a body of a patient; identifying major variations and minorvariations in the raw patient signal, wherein the major variations andminor variations correspond to one or more forces to which the body isexposed, wherein the major variations correspond to a signal of interestportion including physiologically significant information from the rawpatient signal, and wherein the minor variations correspond to minutephysiologically least significant information of an unwanted or leftover signal portion of the raw patient signal; periodically capturingand extracting insignificant data from minor variations that correspondto minute physiologically least significant information of the unwantedor left over signal portion of the raw patient signal unrelated tophysiologically significant major variations of the signal of interestportion, wherein the insignificant data is limited to being extractedfrom portions corresponding to the minor variations, wherein theinsignificant data is used to generate a stimulation signal by tuning astimulation waveform according to the minor variations in the rawpatient signal such that the stimulation waveform is adapted to reducean effect of neural accommodation or adaption, and wherein the use ofthe insignificant data is unrelated to tailoring the stimulation basedon the sensed physiologically significant major variations in the rawpatient signal toward a predefined profile, wherein the stimulationwaveform comprises a series of rectangular pulses, and wherein pulsewidth of the series of rectangular pulses varies over time; and causingan implantable pulse generator to deliver electrical stimulation tobiological tissue that is proximate one or more occipital nerves,wherein to deliver the electrical stimulation, one or more processorscauses the implantable pulse generator to apply the stimulation signalvia one or more leads positioned in contact with or proximate to thebiological tissue.
 17. The method of claim 16, wherein at least one ofan inter-pulse frequency, a pulse amplitude, or the pulse width of theseries of rectangular pulses increases over the time, and wherein adifferent one of the inter-pulse frequency, the pulse amplitude, or thepulse width of the series of rectangular pulses decreases over the time.18. The method of claim 16, wherein the stimulation waveform comprisesone or more relaxation pauses between at least some of the series ofrectangular pulses.
 19. The method of claim 16, wherein an inter-pulsefrequency of the series of rectangular pulses varies over the time. 20.The method of claim 16, wherein an amplitude of the series ofrectangular pulses varies over the time.